A majority of colorectal cancer patients (78%), as demonstrated by our research and the research of others, experience chemotherapy-related cognitive impairment (CRCI); however, interventions to address CRCI in this population are lacking. Main problem areas include difficulty in memory, concentration, attention and executive function. CRCI impairs many facets of quality of life; these effects can last for years in up to 35% of survivors. The etiology of CRCI is not clearly understood, and there are no effective management approaches. Our preliminary work, and that of others, has shown that chemotherapy increases proinflammatory cytokines and that these changes are linked with cognitive impairments in cancer patients during chemotherapy, suggesting that inflammation may contribute to CRCI. If so, interventions that reduce inflammation might alleviate CRCI. Ibuprofen targets many of the same inflammatory cytokine pathways found to be increased in cancer patients, and it can delay the onset or reduce the effects of cognitive impairments in healthy individuals as well as in those at risk for cognitive diseases. Evidence suggests that exercise, which also reduces inflammation, can improve cognitive functioning in healthy adults, in patients with neurodegenerative disease, and those at risk for cognitive decline. Very preliminary research suggests exercise may improve CRCI in cancer patients. Reduction of inflammation with exercise and low-dose ibuprofen is a promising target to alleviate CRCI, particularly during chemotherapy; however, this hypothesis has not yet been tested in colorectal cancer patients. In preparation for this proposal, we conducted a small feasibility randomized clinical trial of an exercise intervention (aerobic and resistance training) and low-dose ibuprofen (200 mg twice daily) for 6 weeks in colorectal cancer patients receiving chemotherapy and showed that both of these interventions are feasible, patients can complete all measures, and that the study evokes high satisfaction. Pilot results from this study suggest that both interventions independently are promising for alleviating CRCI. This innovative R21 proposal builds upon our feasibility trial and includes a three-arm randomized controlled clinical trial comparing the influence of ibuprofen + health education (Arm 1), placebo + exercise (Arm 2) and placebo + health education (control; Arm 3) on CRCI in 84 colorectal cancer patients undergoing adjuvant chemotherapy and experiencing CRCI. The exercise and ibuprofen arms will each be compared to the control (Arm 3) with the primary goal of assessing the preliminary efficacy of each intervention for alleviating CRCI in colorectal cancer patients receiving chemotherapy. We are also assessing whether these interventions influence levels of cytokines and receptors, and whether intervention effects are mediated by inflammation. The study proposal herein is designed to provide critical preliminary information and data to inform an anticipated R01. This study would be one of the first, if not the first, clinical trial to assess interventions for CRCI in colorectal cancer patiets receiving chemotherapy. The benefit of improving CRCI as a result of this study could be considerable.